title: Aryl hydrocarbon receptor-mediated induction of the microRNA-132/212 cluster promotes interleukin-17-producing T-helper cell differentiation.
abstract: Aryl hydrocarbon receptor (AHR) plays critical roles in various autoimmune diseases such as multiple sclerosis by controlling interleukin-17 (IL-17)-producing T-helper (TH17) and regulatory T cells. Although various transcription factors and cytokines have been identified as key participants in TH17 generation, the role of microRNAs in this process is poorly understood. In this study, we found that expression of the microRNA (miR)-132/212 cluster is up-regulated by AHR activation under TH17-inducing, but not regulatory T-inducing conditions. Deficiency of the miR-132/212 cluster prevented the enhancement of TH17 differentiation by AHR activation. We also identified B-cell lymphoma 6, a negative regulator of TH17 differentiation, as a potential target of the miR-212. Finally, we investigated the roles of the miR-132/212 cluster in experimental autoimmune encephalomyelitis, a murine model of multiple sclerosis. Mice deficient in the miR-132/212 cluster exhibited significantly higher resistance to the development of experimental autoimmune encephalomyelitis and lower frequencies of both TH1 and TH17 cells in draining lymph nodes. Our findings reveal a unique mechanism of AHR-dependent TH17 differentiation that depends on the miR-132/212 cluster.
authors.affiliation: Laboratory of Immune Regulation, World Premier International Immunology Frontier Research Center, and Laboratory of RNA Function, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Taisuke
authors.initials: T
authors.lastname: Nakahama
authors.forename: Hamza
authors.initials: H
authors.lastname: Hanieh
authors.forename: Nam Trung
authors.initials: NT
authors.lastname: Nguyen
authors.forename: Ichino
authors.initials: I
authors.lastname: Chinen
authors.forename: Barry
authors.initials: B
authors.lastname: Ripley
authors.forename: David
authors.initials: D
authors.lastname: Millrine
authors.forename: Soyoung
authors.initials: S
authors.lastname: Lee
authors.forename: Kishan Kumar
authors.initials: KK
authors.lastname: Nyati
authors.forename: Praveen Kumar
authors.initials: PK
authors.lastname: Dubey
authors.forename: Kamal
authors.initials: K
authors.lastname: Chowdhury
authors.forename: Yukio
authors.initials: Y
authors.lastname: Kawahara
authors.forename: Tadamitsu
authors.initials: T
authors.lastname: Kishimoto
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation / Q000276:immunology*; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000276:immunology; D020381:Interleukin-17 / Q000276:immunology / Q000378:metabolism*; D008156:Luciferases; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D009841:Oligonucleotides / Q000235:genetics; D051560:Proto-Oncogene Proteins c-bcl-6 / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000378:metabolism
chemical_list: D020381:Interleukin-17; C546976:MIRN132 microRNA, mouse; C554518:MIRN212 microRNA, mouse; D035683:MicroRNAs; D009841:Oligonucleotides; D051560:Proto-Oncogene Proteins c-bcl-6; D018336:Receptors, Aryl Hydrocarbon; D008156:Luciferases
keywords: autoimmunity; dioxin receptor; immune regulation